delta 4-19-nor-17alpha-ethinylandrosten-17beta-ol-3-one and process



United States Patent '0 ammonqnanmvvnmbaosmmins-ons- ONE AND rnocsss s No Drawing. Application November 12, 1952, Serial No. 320,154

Claims priority, application Mexico November 22, 1951 4 Claims. or. 260-4914 The present invention relates to cyclopentanophenam threne derivatives and to a process for the preparation thereof.

More particularly the present invention relates to A--19-nor-androsten-l7p-ol-3-one compounds, having 171:- r'n'ethyl o'r ethinyl substiruents and to a'process for pro ducing these compounds.

In United States application of Dierassi, Rosenkranz and Miramontcs, Serial Number 250,036, filed October 5, 1951, there is disclosed a novel process for the production of 19-norprogesterone. As set forth in this application, l9-norprogesterone has been found to be even stronger in its progestational effect than progesterone itself.

In accordance with the present invention, it has been found that the method described in detail in the aforementioned application may be applied -to produce compounds of the androsten series, namely, A -l9-norandrosten-3,l7-dione. By protecting the 3-keto group of this compound, as by the formation of a suitable enol ether as hereinafter set forth in detail and reacting the resultant 3 enol ether with suitable reagents, there may then be produced A-l9-nor-l7a-methylandrosten-l7fl-ol-3-one or A -19-nor-17a-ethinylandrosten-1743-ol-3-one. The first of these compounds exhibits more pronounced androgenic effects than its homologue methyltestosterone and the second of these compounds exhibits more pronounced progestational effects than its homologue ethinyltestosterone. H

Certain of the novel compounds of the present invention may therefore be represented by the following structural formula: I

I suitable 3 lower alkyl ether as sisting of CECH and CH3.

Compounds as exemplified by the foregoing form'ula cm cm- X o Alkali Metal,

Followed by R0 Acid and O- Oxidation CH E I no --c- =cn 1 Formation OH; H

Addlno 'tionol H Acety- 1 leneor Methyl qrignard, Followed by Acid In the above equation R represents a lower alkyl radi cal, as for example methyl or ethyl, and R represents a lo'weralkyl radical such as ethyl or methyl or abenzyl radical or any of the other groups which are customarily used as part of an enol ether customarily used for the protection of the 34mm group of steroids. Thus, in the alternative rather than an alkyl or benzyl enol ether as shown benzyl thioenolethers may be utilizedin the present reaction or otherthioenolethers.

In practicing the process of the present invention ja for example 3 -rn eth qxy estrone is dissolved in a suitable solvent such as anhydrous dioxane. Thereafter anhydrous liquid ammonia and an alkali metal, such as lithium or sodium metal, are added to the mechanically stirred solution. The stirring is continued for a short period, as for example one hour, and a quantity of ethanol is then added. When the reaction is complete and the blue color produced disappears, water is then added. The ammonia is then evaporated on a steam bath and the product collected with 2.1. of water. Extraction with a suitable solvent, such as ether, and ethyl acetate followed by evaporation to dryness under vacuum, produced a yellow oil. The oil thus obtainedwas then dissolved in a suitable solvent, such as methanol, and refluxed with a mineral acid, such as hydrochloric acid, for approximately one hour. After purifieatiomextraetion and so forth, the product obtained was a yellow oil-having an ultraviolet absorption maximum charaeteristie of.ti- A*-3-ketone. The last-mentioned yellow 'oil .was oxidized as by adding chromic'acidiinl acetic aeid'tb 'l Patented May 1, 1956 -tratetl under vacuum (20 mm.).

stirred solution of the oil in acetic acid at a temperature below- 20 C. Purification of the oxidation product produced A -19-norandrosten-3,17-dione, which was a valuable intermediate for the further steps of the present process.

The 3-keto group of the A-19-norandrosten-3,17-dione could be protected for further steps in the present process by forming a suitable enol ether thereof. For example, by treating the compound with ethyl orthoformate, the A -l9-nor-3-ethoxy-androstadien-17-one was formed. If the 3 enol ether thus formed is then treated with a suitable methyl Grignard reagent, such as methyl magnesium bromide in a suitable solvent, such as anhydrous ether, followed by acidification-with a suitable mineral acid, such as hydrochloric acid, there is then produced a novel A -l9-nor-l7a-methyl-androsten-l7fl-ol-3-one. If, on the other hand, the 3 enol ether is treated with acetylene in the presence of an alkali metal alkoxide, such as potassium tertiary amyloxide, there is formed A -19- nor-l7a-ethinylandrosten-l7p-ol-3-one.

The following specific examples serve to illustrate but are not intended to limit the present invention:

Example I 7.5 g. of 3-methoxyestrone were dissolved in 750 cc. of anhydrous dioxide in a three-neck flask, placed in a box and insulated with cotton wool. 2 l. of anhydrous liquid ammonia and 15 g. of lithium metal in the form of wire were added to the mechanically stirred solution. After stirring for one hour, 150 cc. of absolute ethanol were added at such speed that no bumping occurred; when Example IV A solution of 1 g. of A -l9-nor-3-ethoxy-androstadien- 17-one in 10 cc. of anhydrous ether was added to a solution of 10 g. of methyl magnesium bromide in 25 cc. of anhydrous ether and the mixture was refluxed during two hours and then poured in water, acidified with 50% bydrochloric acid to pH 1 and left standing for one hour. The product was extracted with ether, washed to neutral, dried and evaporated to dryness. Several crystallizations from ether-hexane; yielded A l9-nor-l7a-methylandrosten-l7p-ol-3-one with a melting point of 154 156 C., [al +30.3', ultraviolet absorption maximum at 240;i(log 4.32).

' Example V l g. of potassium metal was dissolved in 25 cc.-of'tertiary amyl alcohol by heating under an atmosphere of nitrogen. 1 g. of A -19-nor-3-ethoxyandrostadien-17- one in 25 cc. of anhydrous toluene was added and nitrogen was passed during 15 minutes. Then acetylene (especially dried and purified) was passed during 14 hours through the mechanically stirred, solution, at room temperature.

I The mixture was poured in water, acidified to pH 1 with the blue color had disappeared, 500 cc. of water were 4 added in the same way. The ammonia was evaporated um chloride solution and extracted with ethyl acetate,

washed to neutral, dried and evaporated to dryness. The product was a yellow oil which showed an ultraviolet ab sorption maximum at 240 (log 14.31), characteristic of a A -3-ketone.

A solution of 2.7 g. of chromic acid in 20 cc. of water and 50 cc. of acetic acid was added to the stirred solution of the above oil in 100 cc. of acetic acid, maintaining the temperature below 20 C. After 90 minutes standing,

50 cc. .of methanol were added and the mixture concentractcd with ether, washed to neutral and evaporated to dryness. The residual semi-crystalline product (7 g.)

was chromatographed over alumina and the fractions eluted with ether yielded 3.2 g. of A -l9-norandrosten- 3,17-dione having a melting point of 163-167 C.

Example II Example III A solution of 2 g. of A -19-norandrosten-3J7-dione and'0.4 g. of pyridine hydrochloride in 50 cc. of benzene The residue was exfree of thiophene was made free of moisture by distilling a small portion 4 cc. of absolute alcohol and 4 cc. of ethyl orthoformate were added and the mixture was refluxed-during 3 hours. 5 cc. of the mixture were then The mixture was evaporated to dryness under vacuum and the residue was taken up in ether, washed, dried and evaporated: to dryness. The residue was crystallized from dilute hydrochloric acid, heated on the steam bath for 30 minutes and then subjected to steam distillation to remove the organic solvents. The residue was filtered, dried and recrystallized several times from ethyl acetate. The M-19-nor-17a-ethinylandrosten-l7fl-ol-3-one thus obtained had a meltingpoint of 198 '-.200' C- (in sulphuric acid bath), 200'-204' C. (Kofler), [elf-31.73, ultraviolet absorption maximum at 240 .(log 438).

We claim:

i 1. A process for theproduction of a compound having the following formula:

which comprises reducing a lower alkyl ether of estrone with an alkali metal in liquid ammonia followed by hydrolysis with a mineral acid and oxidation with chromic acid to' form A -l9-norandrosten-3,17-dione, selectively forming a'3-enol' ether of said dione and treating said ether with acetylene in the presence of analkali metal alkoxide, followed by'hydrolysis with a mineral acid.

2. The process of claim 1 wherein the alkali metal is lithium.

3. The process of claim 1 wherein the alkali metal is sodium.

References Cited in the file of this patent UNITED STATES PATENTS OTHER REFERENCES Jones et al.: IACS, 72, 956-61 (1950). Birch: 'Jour. Chem. Soc., 1950, 367-68. 

4. 1 4-19-NOR-17A-ETHINYLANDROSTEN-17B-01-3-ONE. 